Azacycloheptane compounds and methods for preparing them



United States atent AZACYCLOHEPTANE COMPOUNDS AND METHODS FOR PREPARING THEM Richard F. Tislow, Richard dc Vere Huber, and Julius Diamond, Philadelphia, Pa., assignors to American Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Application September 3,1954,

Serial No. 454,195

9 Claims. (Cl. 260-439) This invention relates to azacycloheptane compounds and more particularly to bis-quaternary salts comprising said heterocyclic rings.

The compounds of the invention fall within the following general formula:

wherein R2 and R3 stand for hydrogen or a lower alkyl, while R4 represents either. hydrogen, cyano, --COO -lower alkyl, -COO-alkali metal, C O-lower alkyl, CONH2, -COOH or --O-CO-lower alkyl.

The compounds of the invention are pharmacologically useful in the veterinary or human field in that they have been found to possess curare-like, musicle-relaxing action among other pharmacological actions. Thus, in com pounds Where R4 represents hydrogen, a ganglionic stimulating action has also been noted. Compounds showing the strongest curate-like action are those where R2 and R3 stand for hydrogen with R4 representing an ester of the COO-lower alkyl type, and with the alkylene chain having from 4 to carbon atoms.

The compounds may be prepared by heating the azacycloheptane with an. alkylene dihalide preferably using a molar ratio of at least 251 azacycloalkane to halide.

It has been found that substantial yields may be achieved .if the reaction takes place in a solvent and if the solvent medium is highly polar, havinga high dielec? tric constant or dipole moment under standard conditions (20 C.) of about 2.5 Debye units or greater. The dielectric constant should be about 10 (epsilon) or greater and preferably from about to 40 when measured under standard conditions. Additionally the highly polar solvent should have a boiling point above about 70 C. since the.reaction goes best and with the greatest yield within.

he aaewfabput 1 0? Q. ltho h h reaction Fee will take place within the range of about 25 to 120 C. Examples of preferred solvents are the nitro and nitrile compounds such as nitrobenzene, nitromethane, nitroethane, l-nitropropane, acetonitrile and benzonitrile. If the precipitate that forms from the aforesaid reaction is large, the reaction mixture is chilled. with ice-water and then treated with a large volume of relatively low boiling ketone, such as acetone or methyl-ethylketone. If little or no precipitate forms, the reaction mixture is treated with a relatively non-polar solvent such as diethylether, heptane or benzene. Surprisingly, an excellent granular product is obtained by adding the reaction mixture gradually to the non-polar solvent, rather than using the re verse procedure.

The desired product obtained as a precipitate is sepa rated from the reaction mixture, washed with non-polar solvent and dried. If further precipitation is sought, the

Ian. 11, 1954. Application Ser. No. 400,136 teaches the methodfor making 4-arylazacycloheptanes having also in the 4-position either hydrogen, CONH2, COOH,

or C OO alkali metal.

To make the 4-arylazacycloheptanes of application Ser.

No. 400,136 one utilizes the corresponding 4 -aryl-4-cyanoazacycloheptane whose general formula is shown in the above mentioned patent and Which .is made as shown by reactions 1, 2 and 3 therein. The cyano substitucnt is hydrolyzed by known procedures to form the amide or --CONH2 radical; Alternatively, the amide may be formed by reacting the 4-cyano compound with a higher alcohol and a base, as for example heptanol and potassium hydroxide at a temperature of about 160 C.

To obtain the carboxylic acid radical, COOH in place of the cyano group, the reaction with alcohol and base as above described is carried out ata higher temperature, in the neighborhoodof 200 C. I-fthe 4-amide compound is reacted With an alkali metal hydroxide alone, the alkalimetal carboxylic acid salt will form. Should one merely Wish to remove the cyano substitucnt, the 4-cyano compound may be heated at about 250 C. in the presence of alkali metal hydroxide and Water. By another procedure, one may decyanate the azacycloheptane by reacting the corresponding 4-cyano compound with an alkali-metal amide in the presence of an inert organic solvent of the hydrocarbon type such as hexane or benzene, or their higher homologues.

The 4-acyloxy azacycloalkanes of application Ser. No. 403,448 may be preparedfrom the corresponding 4-cyanocompounds of Patent No. 2,666,050 described previously. Thus, the cyano compound'is subjected to decyanation as above described and the decyanated product is then reacted with a tetra lead salt of a lower aliphatic carboxylic acid, with the reaction being carried'out in the presence of the corresponding aliphatic acid. As an example, the reaction to replace the cyano radical with the acyloxy radical -OCO-CH is carried out using lead tetra-acetate in the presence of acetic acid as a solvent, the temperature of. reaction being .in the neighborhood of about to C.

The following examples disclose the invention in specific detail. It should be clearly understood that the examples are merely forillustrationand are-notto; be;

construed as lirnitative of the invention.

' 3 EXAMPLE 1 1,4-bis-(4-cyan0-l-methyl-4-phenyl-azacycloheptaneonium) -tetramethylene dibromia'e Analysis.C32H44N4Br2:

Nitrogen, Bromine, percent percent Calcd 8.68 24. 8 Found 8. 96 24. 3

EXAMPLE LS-bis-(4-cyan0-1-methyl-4-phenyl-azacycloheptaneonium -pentamethylene dibromide 4-cyano-l-methyl-4 phenyl azacycloheptane, 2.6 g. (0.012 mole), 1,5-dibromopentane, 1.2 g. (0.0050 mole),

and nitrobenzene, 8 ml., were mixed and heated at 100 C. for 6 hours. After cooling in an ice-bath, acetone,

ml., was added with stirring. The solid, after filtering, was triturated well with dry ether and dried at 50 C. The desired product melted at 205210 C. It may he recrystallized from acetone and methanol (minimum).

Analysis.-C33H4sN4Br2:

EXAMPLE 3 1,4-bis-(1-methyl-4-phenyZ-azacycloheptane-onium tetramethylene dibromide A mixture of 0.05 mole (10.7 g.) 4-cyano-1-methyl-4- phenylazacycloheptane and 0.11 mole (4.3 g.) sodamide in 100 ml. of toluene was refluxed while stirring for 6 hours. The cooled mixture was washed with Water, then the toluene layer extracted with acid, the acid extract washed with ether, treated with sodium hydroxide and the reaction product extracted with ether. The ether extract was dried, filtered, and distilled. The product, 1- methyl-4-phenyl-azacyclophetane was collected at 88- 90,? C. (0.25 mm.); 11 1.5288.

Anal.Calcd. for CiaHisN: C, 82.47; H, 10.12; N, 7.40. Found: C, 82.20; H, 10.41; N, 7.51.

1-methy1-4-phenyl-azacycloheptane, 2.0 g. (0.011 mole) and -1,4-dibromobutane, 1.1 g. (0.0050 mole) in 8 ml. of acetonitrile were heated at 82 C. for about 3 hours. White crystals appeared. The mixture was cooled, filtered and washed with acetone-ether on the filter. -It was dried overnight. This gave a white solid that melted at 223- C.

a; EXAMPLE 4 1 ,5 -bis- 1 -methyl-4-phenyl-azacycloheptane-onium pentamethylene dibromide 1-methyl-4-phenyl-azacycloheptane 2.0 g. (0.011 mole) and 1,5-dibromopentane, 1.2 g. (0.0050 mole) in 8 ml. of benzonitrile were heated at 100 C. for about 3 hours. White crystals appeared after [first 5 minutes. After cooling to room temperature, it was treated with acetone with stirring, filtered, and washed 0n the filter with acetone and ether. This gave a white solid product that was recrystallized from a mixture of acetone and methanol (minimum) and melted at 238-239 C.

/ Nitrogen, Bromine,

percent percent Calcd 4. 61 26. 3 Found 4. 85 26. 6

Nitrogen, percent Bromine, percent Calcd 4. 52 Found 4.

Silver nitrate, 0.55 g. (0.0032 mole), in 10 ml. of distilled water was added dropwise with stirring to 1.0 g. (0.0016 mole) of 1,6-bis-(4-phenyl-1 methyl azacycloheptaneonium)-hexamethylene dibromide in 25 ml. of distilled water at room temperature. After stirring 15 minutes more, the mixture was filtered. The water of the clear filtrate was removed under a pressure of 10 mm. and heated with a hot water bath. The residue was made granular by trituration with anhydrous ether, filtered, and dried over P205 at 25 C. (5 mm.). The water soluble product started to melt at 750 C.

Analysis for Cad-150N406:

Carbon Hydrogen Nitrogen Calcd Found Nitrogen, Bromine, Nitrogen, Bromine, percent percent percent percent Oalc 4. 71 26. 9 Calcd 3. 79 21. 7 Fo 4. 39 27. 5 Found 4. 32 21.8

EXAMPLE 7 i ,5 -bis-'(4-carbethoxy-4-phenyl-1 -methyl-azacycloheptane-onium -pentamethylene dibromide Nitrogen, Bromine, percent percent l Caled 3. 72 l 21. 3 Found 4. 08 I 20.

EXAMPLE 8 1,6 bis-(4-carbeth0xy-1-melhyl-4-phenyl-azacylohepzaneoniumyhexamethylene dibromia'c 4-carbethoxy-l-methyl-4'phenyl-azacycloheptane, 2.6 g. (0.010 mole), 1,6-dibromohexane, 1.2 g. (0.0050 mole) and nitrobenzene, 5 rnl., were mixed and heated for 5 hours at 100 C. The resultant solutionwas treated with ether (after cooling) in order'to' precipitate the product which was then triturated well and dried under ether. This gave the desired product that began to melt-at 65 Nitrogen, "Bromine, percent percent Calcd. 3,65 '20. 9 Found 3. 54 20. 6

EXAMPLE 9 1 7-bis- (4 -carbeth oxy-l -methyl-4pheny l-azacyclohep tmze onz'umQ-heptamethylene dibmmide 4-carbethoxy-lsmethyl-4-phenyl-azacycioheptane, 2.6 g. (0.010 mole), 1,7-dibromoheptane, 1.3 g. (0.0050 mole), and nitrobenzene, 4 rnl., were mixed and heated 18 hours at 100 C. After cooling in an ice-bath, the reaction mixture was diluted with 30 ml. of acetone and added dropwise to ether with continuous stirring. The precipitate was washed and driedund'er ether for 5 days. This. gave the product that began to melt at 85 C.

Nitrogen, Bromine, percent percent Color! 3. 59 20. 5 Found 3. 35 f 19. 3

EXAMPLE .10

] ,8-I1is- (4-carherlz0xy-1-1nethyl-4-pizertylmzacyclohepmneonirmz)-0ctam=ethylene dibronride Analysis-CmHezNaQBm:

Nitrogen,

percent Calod 3. 62 20. 1 Found 3. 50 18. 3

EXAMPLE 1 1 1 ,1 0-bir-(4-carbelh0xy 1 methyl 4 az acyclo heptaneoniumydecum ethylene diioalide 4-carbethoxy-1-methyl-4-phenyl-azacycloheptane, 2.9 g. (0.011 mole), 1,10-diiododecane, 2.0 g. (0.0050 mole), and nitrobenzene, 5 rnl., Weremixed together and heated 15 hours at 100 C. After cooling down to 5 C. and mixing well with acetone some crystallization began. But after cooling down with a Dry-Ice and acetone bath and adding dry ether gradually, the main body of the product came out of solution at a faster rate. It was filtered oif, washed with ether, and then reprecipitated by adding its solution in acetone-methanol (minimum) dropwise to stirred ether. The product melted at 190-195 C.

Nitrogen, percent Iodine. percent EXAMPLE 12 1 ,4-bis- ('4-cyan0-1 ,Z-a'imethyl-4-phenyl-azacycloheptanw Ortiz/m)detramethylene a'ibromirle To a solution of 1.43 moles (167.6 g.) of phenylacetoni- 'trile in 250 ml. of toluene was added 1.29 mole (50.3 g.) of sodamide at such a rate as tornaintain the temperature at 35-40". The addition was efi'ected under a nitrogen atmosphere with stirring. .After an additional 2 hours at 35-40, the mixture was cooled to 5. A dry toluene solution of 1-dimethylamino-Z-chloropropane, prepared the same day from 1.23 moles (193 g.) of the hydrochloride and 1.37 moles (54.6 g.) of sodium hydroxide in 500 ml. of water and 250 ml. of toluene, was then added dropwise at 540". This temperature was main tained an additional hour, then it was allowed to rise to room temperature and stand overnight. The mixture was washed with water, extracted with 6 .N-hydrochloric acid, the acid extract washed with ether, basified, andextracted with ether. The ether extract was dried, filtered, and distilled. A mixture of the isomers of the butyronitriles boiled at 8 (0.2 mm), 21 1.5028.

To a stirred solution of 0.85 mole (172.8 -g.) of a mixture containing 4-dimethylamino-3- and 4--methyl-.2-phenyl-n-butyronitrile in 1.2 l. of toluene under a nitrogen atmosphere, was added portionwise 1.09 mole (42.6 g.'), of sodamide. The rate of addition was controlled so as to maintain the temperature at 35-40". This temperature was kept an additional 2 hours. The red solution was cooled to 30 in a Dry Ice-acetone bath, and 0.898 mole (141.3 g.) of trimethylene chlorobromide in 250 ml. of toluene was added at such a rate as to maintain the temperature between -25 and -15 This temperature was maintained an additional /2 hour, "then the stirred mixture was allowed to warm to room temperature and stand over night. The mixture was filtered and the toluene distilled from the filtrate at 30-35 (35 mm). The liquid residue contained a mixture of the land .Z-methyl chlorhexanes.

Liquid residue from the preceding step was diluted to 850 ml. with nitrobenzene and the resulting solution heated at for 17 hours to precipitate the quaternary salt. The cooled mixture wasfiltered and the precipitate washed several times with acetone to give essentially pure Q-methyl quaternary salt, M. P. 251-251.5-deo. Recrystallization from ethanol gave fine white crystals, M. P. 259 dec.

Anal.-Calcd. for CmHzaCINz: C, 69.00; H, 8.32; N, 10.05 ;Cl, 1 2,70. Found: C, 68.46; H, 8.73; N, 10.29; C1, 12.14. I

v The filtrate from the quaternary salt contained the 2- 'methyl chlorhexane unchanged.

filtered, and the solvent removed. I

Distillation of the liquid residue gave the Z-methyl cyano ba'se, B. P. 123-6 (0.2 mm.), 11 1.5341, 10. 1.019.

Anal.Calcd. for C15H20N2Z C, 78.90; H, 8.83; M 69.54. Found: c, 78.50; H, 8.78; M 69.40.

4-cyano-1,2-dimethyl-4-phenyl-azacycloheptane, 2.3 g.

(0.010 mole), 1,4-dibromobutane, 0.86 g. (0.004 mole), and nitrobenzene, 7.5 ml., were mixed and heated 23 hours at 100 C. Crystals appeared. At room temperature, 50 ml. of dry ether was added with good stirring, the mixture was filtered, and the solid was washed with acetone and then ether by trituration. After drying, there was obtained the desired product that began to melt at 200 C.

EXAMPLE 13 1,5-bis- (4-cyan0-L2-dimethyl-4-phenyl-azacyclohepraneonium)-pentamethylene dibromide 4-cyano-1,2-dimethyl-4-phenyl-azacycloheptane, 2.3 g. (0.010 mole), 1,5-dibromopentane, 0.92 g. (0.004-0 mole), and nitrobenzene, 7.5 ml., were mixed and heated 23 hours at 100 C. No crystals; At room temperature, 50 ml. of

ether was added gradually with good stirring to precipitate the product which was then reprecipitated from acetonemethanol (minimum) with ether and finally dried under ether. The product started to melt at 100 C.

Analysis.C3 4H4sN4Br2 EXAMPLE 14 1,4-bis-(1,2-dimethyl-4-phenyl-azacycloheptane-0nium) tetra-methylene dibromide In the same manner as taught in Example 3, and starting with 0.05 mole (11.4 g.) of 4-cyano-1,2-dimethyl-4- phenyl-azacycloheptane, one may obtain the free base 1,Z-dimethyl-4-phenylazacycloheptane, B. P. 106-108 C. (0.2 mm.), n 1.5255.

Anal.-Calcd. for C14H21N: C, 82.65; H, 10.40; N, 6.88. Found: C, 82.25; H, 10.35; N, 6.66.

1,Z-dimethyl-4-phenyl-azacycloheptane, 2.0 g. (0.010 mole), 1,4-dibromobutane, 1.1 g. (0.0050 mole), and nitrobenzene, 3 ml., were mixed and heated hours at 100 C. The crystalline mass was cooled down to room temperature, mixed with acetone, and filtered. The solid was washed and dried under ether. The product started to melt at80 C.

Analysis.-Ca2HsoN2Bra:

I Nitrogen, Bromine,

percent percent Calcd 4. 51 25. 8 Found 4. 57 23. 3

EXAMPLE 15 1,5-bis-(1 ,2dimethyl 4-phenyl-azacycloheptane-onium penta-methylene dibromide 1,2-dimethy1-4-phenyl-azacycloheptane, 2.0 g. (0.010 mole), 1,5-dibromopentane, 1.2 g. (0.0050 mole), and nitrobenzene, 3 ml., were mixed and heated 20'hours at C. The solution that resulted was cooled'to 25 C. and diluted with acetone. By adding a large volume of ether to this, the product was precipitated. After washing and drying with ether, the desired product started to melt at 75 C.

A nalysis.--C33H52N2B r2 Nitrogen, Bromine, percent percent Calcd 4. 41 25.2 Found 4. 34 21. 9

EXAMPLE 16 l ,4-bis- (1 ,3-dimethyl-4-phenyl-azacycloheptane-onium) tetra-methylene dibromide Following the procedure of Example 3, and starting with 0.05 mole (11.4 g.) 4-cyano-1,3-dimethyl-4-pheny1- azacycloheptane, the product obtained is 1,3-dimethyl-4- phenylazacycloheptane, B. P. 98100 C. (0.25 mm.), 11, 1.5251.

Anal.Calcd. for C14H21N: C, 82.65; H, 10.40; N, 6.88. Found: C, 82.06; H, 10.35; N, 6.60.

1,3-dimethyl4-pheny1-azacycloheptane, 2.1 g. (0.010 mole) 1,4-dibromobutane, 0.86 g. (0.0040 mole), and nitrobenzene, 5 ml. were mixed and heated 21 hours at 100 C. After cooling the crystalline mass to 25 C., it was mixed with a large volume of acetone and allowed to stand 16 hours. It was then filtered, and the solid was washed and dried under ether. The product melted at 216218 C. with decomposition.

Analysis.C32HeoN2Br2:

1,3-dimethyl-4-phenyl-azacycloheptane, 2.1 g. (0.010 mole), 1,5-dibromopentane, 0.92 g. (0.0040 mole), and nitrobenzene, 5 ml., were mixed and heated 21 hours at 100 C. After cooling the crystalline mass to 25 C., it was mixed with a large volume of acetone and allowed to stand overnight. It was then filtered, and the solid was washed and dried under ether. The dibromide melted at 213-215 C. with decomposition.

Analysis.,Cs3H52N2Br2:

Nitrogen, Bromine, percent percent Calcd 4. 41 25. 2 Found 4. 24 25.0

Silver sulfate, 0.31 g. (0.0010 mole), in 75 ml. of warm distilled water was added dropwise with stirring to 0.65 g. (0.0010 mole) of 1,5-bis-(1,3-dimethyl-4-phenyl-azacycloheptane-onium)-pentamethylene dibromide in 20 ml. of distilled water at room temperature. After stirring 15 minutes more, the mixture was filtered. The water of the clear filtrate was removed under a pressure of mm. and heated with a hot water bath. The residue was dissolved in an acetone-methanol mixture, filtered through carbon black, and the clear filtrate added dropwise with stirring to a large volume of ether. The precipitate was made granular by trituration with dry ether. After filtering and drying over P205 at 25 C. (5 mm.), the water-soluble sulfate salt was obtained which started to melt at 70 C.

Analysis for C33H52N204S:

Carbon Hydrogen Nitrogen Sulfur Oalcd 69. 3 9. 16 4. 90 5. 60 Found 65. 9 9. 37 4.35 4. 91

EXAMPLE 18 1,6-bis-(1 ,2-dimethyl-4-phenyl-azacycloheptane-onium hexamethylene dibromide Nitrogen, Bromine, percent percent Oaled 4. 31 24. 6 Found 4. 93 24. 3

EXAMPLE 19 1,4-bis- (4-carbethoxy-1-methyl-4-phenyl-azacycloheptaneonium)-1-methyl-tetramethylene dibromid e 4-carbethoxy-1-methyl-4-phenyl-azacycloheptane, 2.6 g. (0.010 mole), 1,4-dibromopentane, 1.1 g. (0.0050 mole), and nitrobenzene, 4.0 ml., were mixed and heated 20 hours at 90100 C. After cooling down to room temperature, it was diluted with 25 ml. of acetone. The clear yellow solution was added dropwise with stirring to 200 ml. of anhydrous ether over a period of 2 hours to precipitate a solid product. The supernatant solution was decanted, and the yellow solid was Washed and dried under ether for 2 days. After drying at 25 C. (5 mm.) over P205 the product obtained began to melt at 70 C.

Analysis.Ca 'rHssNzO rBrz Nitrogen, Bromine, percent percent Calcd 3. 73 21.3 Found 4. 37 21. 1

EXAMPLE 20 10 20 hours at -100 C. After cooling down to room temperature, it was diluted with acetone, filtered, and the clear filtrate added dropwise with good stirring to a large volume of dry ether. The white precipitate was washed well with ether by trituration and dried over P205. The product started to melt at 140 C. Analysis for C41Hs4BrzN2O4:

Nitrogen, Bromine, percent percent Galed 3. 46 19. 8 Found 3. 60 18. 7

We claim:

1. A quaternary ammonium salt containing the cation 0 O Odower alkyl lower alkyl- 0 O C CaHs -CH2CH: CH:CHn-CCOHs and an alkylene dihalide reactant having from 6 to 10 carbon atoms, said solvent having a boiling point above about 70 C. and a dipole moment of at least about 2.5 Debye units, heating the reactants to a temperature in the range of about 70 to about C. thereby forming as a desired product a quaternary ammonium salt containing the cation C O 0 -lower alkyl CsHsC-CHz-C.Hr CHr-ClHr-C-COH5 Nelk-N CHr- 2-CHz lower alkyl- 0 O C wherein alk stands for an alkyleen radical of 6 to 10 carbon atoms.

8. The process of claim 7, wherein the reaction products are commingled with a relatively non-polar solvent thereby precipitating the desired product.

9. The process of claim 8, wherein the reaction products are gradually added to said relatively non-polar solvent.

References Cited in the file of this patent UNITED STATES PATENTS Diamond et a1 Jan. 12, 1954 Slack et al Jan. 26, 1954 OTHER REFERENCES MacArdle: Use of Solvents in Synthetic Org. Chem." (Van Nostrand) pp. 151-5 (1925).

Collier et al.; Nature, vol. 164, pp. 491-2 (1949).

Jones, Chem. Abst., vol. 45, col. 619 (1951). 

1. A QUATERNARY AMMONIUM SALT CONTAINING THE CATION 